Eight-year progression of leukoencephalopathy with calcifications and cysts in a patient with Labrune syndrome who underwent multiple surgeries: A case report

Eight-year progression of leukoencephalopathy with calcifications and cysts in a patient with Labrune syndrome who underwent multiple surgeries: A case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Eight-year progression of leukoencephalopathy with calcifications and cysts in a patient with Labrune syndrome who underwent multiple surgeries: A case report Lei Lou, Shixuan Du, Yi Xing, Xiaolei Song, Xiaoye Liu, Yuehong Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9133567/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Background Leukoencephalopathy with intracranial calcifications and cysts (LCC), also known as Labrune syndrome, is a rare genetic microangiopathy caused by biallelic mutations in SNORD118 . The mechanisms by which loss-of-function mutations in SNORD118 develop into leukoencephalopathy, calcifications, and intracranial cysts remains unknown. Case Presentation: We report the case of a 54-year-old woman with LCC who was admitted for an acute onset of epilepsy for 5 days. She had a history of intermittent resection of multiple intracranial space-occupying lesions for 8 years and epilepsy for 5 years. She underwent four neurosurgical interventions over an 8-year period. We obtained the pathological sections from these four surgeries and retrospectively analyzed the pathological progression of LCC. Histopathological analysis revealed that angiomatoid hyperplasia was an early histomorphological manifestation of LLC, suggesting that it induced changes in the surrounding brain tissue, aggregation of phagocytes, and subsequent cystic lesions. Conclusions The basic histopathological abnormalities of LCC were angiomatoid hyperplasia and obliterative microangiopathy. The 8-year follow-up revealed gradual cyst enlargement (likely from edematous microcyst fusion) and microangiopathic progression (from angiomatous proliferation to vascular sclerosis, obliteration, ischemia, and cyst formation), supporting the pathogenesis of microangiopathy-driven ischemia and cyst formation. Labrune syndrome Leukoencephalopathy Intracranial cysts Intracranial calcifications Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Leukoencephalopathy with intracranial calcifications and cysts (LCC), also known as Labrune syndrome, is a rare hereditary cerebral microangiopathy that was first reported by Labrune et al. [ 1 ] in 1996. It is characterized by a neuroimaging triad of diffuse and asymmetric leukoencephalopathy, extensive cerebral calcifications, and parenchymal brain cysts. The core clinical manifestations of LCC include progressive pyramidal or cerebellar signs, cognitive impairment, and epileptic seizures [ 2 – 4 ]. Although most patients present during childhood or young adulthood, several cases of late, adult-onset LCC have been reported [ 5 – 7 ]. Histopathologically, angiomatous changes and cystic gliotic lesions are the pathological hallmarks of LCC [ 6 , 8 ]. Recently, Jenkinson et al. [ 9 ] identified biallelic variants in the SNORD118 gene as the underlying cause of LCC. Here, we report a case of LCC in a Chinese woman who underwent five brain surgeries over an 8-year period, to describe the pathological progression of LCC over time. The results are reported according to the CARE guidelines. Case presentation A 54-year-old woman was admitted to our hospital via the emergency unit in May 2025 because of status epilepticus. She reported experiencing impairments in memory and concentration. Although she had no family history of a hereditary disease or similar illness, the multidisciplinary neuro-oncology team at our center had suspected LCC and recommended genetic testing 5 years previously; however, the patient had declined. In March 2021, cerebral magnetic resonance imaging (MRI) had revealed multiple cysts, calcifications, and diffuse asymmetric white matter lesions (Fig. 1 a–d). In 2025, cerebral MRI revealed progression and enlargement of the asymmetric white matter lesions, with additional cysts (Fig. 1 e–h). The patient had undergone craniotomies in September 2017, August 2019, November 2019, and October 2024 (Fig. 2 ). The first craniotomy, in September 2017, was to remove lesions in the left temporal lobe that had been discovered on diagnostic imaging. In August 2019, a large cerebellar cyst was surgically removed because of clinical signs of increased intracranial pressure. The patient subsequently experienced an intracranial hemorrhage, and a left parietal lobe cyst was removed in November 2019. In early 2020, 3 months after the third surgery, the patient developed epileptic seizures, bradyphrenia, and memory impairment and was admitted to our hospital for further evaluation and treatment. Initially, the seizures were infrequent and responded well to anticonvulsant therapy. However, new cysts subsequently appeared, and the patient developed progressive motor symptoms, manifesting as right-sided weakness and slurred speech. She had been diagnosed with hypertension in 2023, with intermittent unstable blood pressure, but had not received antihypertensive medication. In October 2024, she had undergone a decompressive craniectomy at another hospital to resect an intracranial space-occupying lesion owing to severe midline shift of the brain. Owing to imaging results and the status epilepticus, resection of the left parietal lesion was recommended, with concurrent cranioplasty of the right temporal and parietal regions. The patient subsequently underwent a fifth surgery in our hospital in May 2025. Histopathologic examination of brain tissue from the fifth surgery revealed white matter with a spectrum of microangiopathic changes. The cerebral white matter exhibited angiogenesis and hemorrhage, with changes ranging from dilated vessels with thickened and hyalinized walls to severely sclerotic vessels with mural deposition of fibrinoid material and varying degrees of stenosis, as well as a few obliterated vessels (Fig. 3 a–c). Additionally, the walls of the blood vessels showed signs of acute and chronic inflammatory cell infiltration, with perivascular lymphocytic cuffing (Fig. 3 d, e). Other changes to the white matter included microhemorrhage, intense gliosis, and multiple foam cells around the damaged vessels, with focal formation of Rosenthal fibers (Fig. 3 f–h). Scattered microcalcifications were also present (Fig. 3 i). CD34 staining revealed abundant small blood vessels within the cyst wall (Fig. 3 j), whereas neurofilament and Luxol Fast Blue staining revealed partial myelin and axon loss, respectively (Fig. 3 k, l). We subsequently conducted a retrospective analysis of pathological sections from the first four surgeries. The chief histopathological findings in the first surgery were angiomatous changes in the form of abnormal prominent congested vessels, with hyaline changes in the blood vessel walls (Fig. 4 a–c). Tissue resected during the second surgery to remove the cerebellar space-occupying lesion showed angiomatoid areas and dystrophic calcification in the cerebral parenchyma and vessel walls (Fig. 4 d–f). Postoperative pathology of brain tissue resected during the third and fourth surgeries revealed multiple dilated and congested blood vessels as well as angiomatoid areas (Fig. 4 g–i). These pathological findings were consistent with a diagnosis of LCC. Discussion Compared with other hereditary cerebral small-vessel diseases, LCC is clinically heterogeneous, with a highly variable disease course [ 2 ]. Headache is the most common neurological symptom because of the increased intracranial pressure resulting from the mass effect induced by cysts, hemorrhage, and cerebral edema. Other common clinical manifestations include hemiplegia and epilepsy [ 2 ], as in our patient. Although LCC generally shows a slowly progressive clinical course, neuroimaging reveals severe and progressive degenerative changes in the nervous system. The commonly described neuroimaging features of LCC include diffuse bilateral cerebral white matter hyperintensity on T2-weighted imaging (particularly around cysts), increased white matter signal intensity with relative sparing of U-fibers and the corpus callosum, and extensive coarse calcifications in the basal ganglia and brain stem [ 10 – 12 ]. LCC has diverse histological manifestations. Its key histological characteristics include angiomatoid hyperplasia, thickening and degeneration of blood vessel walls, lymphocyte aggregation, and glial cell proliferation. Phagocytes accumulate around the blood vessels in brain tissue, accompanied by hemosiderin deposition, scattered microcalcifications, gliosis, formation of Rosenthal fibers and eosinophilic bodies, and demyelination. These changes further lead to cerebral tissue degeneration, necrosis, calcification, and hemorrhage [ 2 , 3 , 7 , 9 ]. This case demonstrates the progressive histopathological changes of LCC, specifically the microcystic degeneration caused by persistent and diffuse cerebral microangiopathy, as well as the degeneration of brain tissue induced by the microcystic changes. The slow disease progression in our patient is consistent with the reported slow progression of LCC [ 2 ]. Over the 8-year clinical course, many of the intracranial cysts gradually enlarged, causing a mass effect and compressing adjacent structures such as the ventricles and cerebral peduncles. The enlargement of the cysts may be attributed to the continuous accumulation of fluid in the white matter. Serial histomorphological observations from four consecutive surgeries revealed cystic dilatations of varying sizes in the patient’s brain tissue, which enabled us to assess the process underlying cyst formation. The cyst walls were composed of brain tissue, with no lining cells in the cavities. The coalescence of microcysts containing edematous fluid probably contributed to cyst enlargement. The main histopathological findings included edematous changes in the cerebral parenchyma, excessive proliferation of abnormal small blood vessels, gliosis, and microcalcifications. The histopathological findings from the first three surgeries showed mainly angiomatous changes including prominent congested blood vessels, multiple cystic areas, foci of dystrophic calcification in the cerebral parenchyma, numerous foci of gliosis, Rosenthal fibers, and histiocytic aggregates. However, pathological sections from the fifth surgery showed no angiomatous proliferation of small blood vessels, but the histopathological changes ranged from dilated blood vessels with thickened and hyalinized walls to severe sclerosis of the vessels with mural deposition of fibrinoid material and varying degrees of stenosis, with a few obliterated vessels accompanied by myxoid changes in the neuropil. Numerous hemosiderin-laden macrophages indicated chronic microhemorrhage. Damaged blood vessels were often associated with perivascular myelin and axonal loss, consistent with ischemic changes rather than demyelination alone. This spectrum of microangiopathic changes suggests a temporal sequence, with vascular sclerosis, obliteration, ischemia, and cyst formation as the final steps. Conclusion This 8-year follow-up of a case of LCC confirms its indolent course, gradual cyst enlargement, and a spectrum of progressive microangiopathic changes suggestive of microangiopathy-driven ischemia and cyst formation. This case provides novel insights into the progression of the pathology of LCC. Abbreviations LCC Leukoencephalopathy with intracranial calcifications and cysts MRI Magnetic resonance imaging Declarations Ethics approval and consent to participate The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the First Hospital of Hebei Medical University. Consent for publication Written informed consent has been obtained from the patient to publish her case details and the associated images. Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Competing interests The authors declare that they have no competing interests. Funding The work was supported by Foundation for Excellent Clinical Medical Talent Project of Hebei Province, China [grant number ZF2024036], the Medical Science Research Program of Hebei Province, China [grant number 20260349], and the Science and Technology Program of Hebei Province, China [grant number 236Z7747G]. Authors’ contributions LL conceptualized the paper. SD, YX, XS, and XL collected the data. LL wrote the original draft, and LL and YL revised the manuscript. All authors read and approved the final manuscript. Acknowledgments Not applicable. References Labrune P, Lacroix C, Goutières F, de Laveaucoupet J, Chevalier P, Zerah M, et al. Extensive brain calcifications, leukodystrophy, and formation of parenchymal cysts: a new progressive disorder due to diffuse cerebral microangiopathy. Neurology. 1996;46:1297–301. doi:10.1212/WNL.46.5.1297. Paff M, Samuel N, Alsafwani N, Paul D, Diamandis P, Climans SA, et al. Leukoencephalopathy with brain calcifications and cysts (Labrune syndrome) case report: diagnosis and management of a rare neurological disease. BMC Neurol. 2022;22:10. doi:10.1186/s12883-021-02531-y. Corboy JR, Gault J, Kleinschmidt-DeMasters BK. An adult case of leukoencephalopathy with intracranial calcifications and cysts. Neurology. 2006;67:1890–2. doi:10.1212/01.wnl.0000244470.06748.18. Armstrong MJ, Hacein-Bey L, Brown H. Cerebroretinal microangiopathy with calcifications and cysts: demonstration of radiological progression. J Comput Assist Tomogr. 2009;33: 571–2. doi:10.1097/RCT.0b013e31818c0957. Coeytaux A, Lobrinus JA, Horvath J, Kurian M, Vargas MI. Late onset of leucoencephalopathy with cerebral calcifications and cysts. J Neuroradiol. 2011;38: 319–20. doi:10.1016/j.neurad.2010.08.004. Kaffenberger T, Valko PO, von Meyenburg J, Baráth K, Hewer E, Heppner FL, et al. A case of late onset leukoencephalopathy with cerebral calcifications and cysts in a 59-year-old woman. Eur J Neurol. 2009;16: 278–81. doi:10.1111/j.1468-1331.2008.02392.x. Ummer K, Salam KA, Noone ML, Pradeep Kumar VG, Mampilly N, Sivakumar S. Leukoencephalopathy with intracranial calcifications and cysts in an adult: case report and review of literature. Ann Indian Acad Neurol. 2010, 13, 299–301. doi:10.4103/0972-2327.74198. Nagae-Poetscher LM, Bibat G, Philippart M, Rosemberg S, Fatemi A, Lacerda MT, et al. Leukoencephalopathy, cerebral calcifications, and cysts: new observations. Neurology. 2004;62:1206–9. doi:10.1212/01.WNL.0000119341.59445.CF. Jenkinson EM, Rodero MP, Kasher PR, Uggenti C, Oojageer A, Goosey LC, et al. Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts. Nat Genet. 2016;48:1185–92. doi:10.1038/ng.3661. Sener U, Zorlu Y, Men S, Bayol U, Zanapalioglu U. Leukoencephalopathy, cerebral calcifications, and cysts. AJNR Am J Neuroradiol. 2006;27:200–3. Ma Y, Zhang X, Cheng C, Xu Q, Di H, Zhao J, et al. Leukoencephalopathy with calcifications and cysts: a case report. Med (Baltim). 2017;96:e7597. doi:10.1097/MD.0000000000007597. Stephani C, Pfeifenbring S, Mohr A, Stadelmann C. Late-onset leukoencephalopathy with cerebral calcifications and cysts: case report and review of the literature. BMC Neurol. 2016;16:19. doi:10.1186/s12883-016-0543-1. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 26 Apr, 2026 Reviews received at journal 24 Apr, 2026 Reviews received at journal 20 Apr, 2026 Reviewers agreed at journal 19 Apr, 2026 Reviewers agreed at journal 16 Apr, 2026 Reviewers agreed at journal 15 Apr, 2026 Reviewers agreed at journal 15 Apr, 2026 Reviewers invited by journal 15 Apr, 2026 Editor invited by journal 20 Mar, 2026 Editor assigned by journal 17 Mar, 2026 Submission checks completed at journal 17 Mar, 2026 First submitted to journal 16 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9133567","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":611663574,"identity":"1b529cc6-cee4-4da0-8dd8-6ec7e647aac3","order_by":0,"name":"Lei Lou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYBACfvb+Bwc/GNTI8UswsEGEDhDQItlzhvGxRMExY8kZxGoxuJHDbMDzgTlxww1itTCcOXtMQsKALXHz7eZjj262Mcjx3Uhg/FyARwdje1+aRIGBjPG2O8fSjXPbGIwlbyQwS8/Ao4WZ54AZyBbZbTdyzKSBWoAuTGBj5sGjhU0iwUyCx4CZcfOM/G8gLfUEtfBI5BgbALUobpDIYQNpSTAgpEWC51jiYwmDY8YSN9LMjXPOSRjOPPOwWRqfFvvjzQcOfvgDjMoZyc8e55TZyPMdTz74GZ8WDFuBmLGBBA2jYBSMglEwCrABAGesTe3ZHmS4AAAAAElFTkSuQmCC","orcid":"","institution":"First Affiliated Hospital of Hebei Medical University","correspondingAuthor":true,"prefix":"","firstName":"Lei","middleName":"","lastName":"Lou","suffix":""},{"id":611663578,"identity":"fa2a1705-3200-43bc-8c6f-b2db30945587","order_by":1,"name":"Shixuan Du","email":"","orcid":"","institution":"Second Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shixuan","middleName":"","lastName":"Du","suffix":""},{"id":611663584,"identity":"2c8df790-5c9c-49c2-8528-c9fa9ef35ba6","order_by":2,"name":"Yi Xing","email":"","orcid":"","institution":"Second Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yi","middleName":"","lastName":"Xing","suffix":""},{"id":611663590,"identity":"10f76b68-cf17-4e1c-8b53-45194715aedf","order_by":3,"name":"Xiaolei Song","email":"","orcid":"","institution":"Second Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaolei","middleName":"","lastName":"Song","suffix":""},{"id":611663592,"identity":"c975b78d-5821-4ae8-a025-c2451921f172","order_by":4,"name":"Xiaoye Liu","email":"","orcid":"","institution":"Second Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoye","middleName":"","lastName":"Liu","suffix":""},{"id":611663594,"identity":"98a0e326-7c41-4143-9167-b2178aa50137","order_by":5,"name":"Yuehong Li","email":"","orcid":"","institution":"Second Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuehong","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2026-03-16 06:09:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9133567/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9133567/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106348682,"identity":"fd2acda5-f922-4421-9169-fbb16d420812","added_by":"auto","created_at":"2026-04-07 16:49:30","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":255395,"visible":true,"origin":"","legend":"\u003cp\u003eBrain magnetic resonance imaging (MRI) findings in 2021 (top row) and 2025 (bottom row). (a) T1-weighted imaging shows multiple hypointense intracranial lesions with relatively clear boundaries. (b) T2-weighted imaging shows lesions with hyperintense signals surrounded by ill-defined zones of edema. (c, d) Contrast-enhanced sequences show lesions with ring enhancement and some lesions with solid enhancement. (e) T1-weighted imaging shows an increase in the extent of the lesion; cystic dilatation is visible in the body and posterior horn of the bilateral lateral ventricles, with widened ventricular morphology. (f) T2-weighted imaging shows an increase in the size of the hyperintense lesions and increasingly marked surrounding edema with compression of the surrounding brain parenchyma. (g, h) The enhancement pattern of the lesions is similar to that of the previous images (c and d), still showing ring or solid enhancement; however, the mass effect of the lesions on the intracranial structures is more marked.\u003c/p\u003e","description":"","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9133567/v1/ff5b38b9f8978d919821621f.jpg"},{"id":106348684,"identity":"199062d7-df1c-4bb0-b6af-acee8977689e","added_by":"auto","created_at":"2026-04-07 16:49:30","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":117930,"visible":true,"origin":"","legend":"\u003cp\u003eTimeline of the surgeries and clinical progression.\u003c/p\u003e","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9133567/v1/4fa581a72cf3fc61c9a3e4d9.jpg"},{"id":106348683,"identity":"08e97255-4077-4f8a-88a2-be7044f83963","added_by":"auto","created_at":"2026-04-07 16:49:30","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":684412,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathology of the brain lesions based on specimens obtained during the fifth brain surgery in May 2025. (a, b, c) Histopathology showing vascular changes in the white matter. (d, e) Perivascular inflammatory cell infiltration. (f, g) Aggregation of perivascular macrophages and intraparenchymal macrophages in the white matter. (h) Foci of gliosis and Rosenthal fibers. (i) Dystrophic calcification in the cerebral parenchyma. (a–i all hematoxylin and eosin stain.) (j) CD34 staining demonstrated vascular profiles. (k) Neurofilament staining suggested relative preservation of axons. (l) Luxol Fast Blue staining. indicated myelin loss\u003c/p\u003e","description":"","filename":"figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9133567/v1/ada21af8c2b38f96e86da851.jpg"},{"id":106348685,"identity":"496c52f0-fb1c-4f69-a070-6bd8d085030c","added_by":"auto","created_at":"2026-04-07 16:49:30","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":935274,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathology of brain tissue from the first four surgeries showing the progression between September 2017 and October 2024.\u003cstrong\u003e \u003c/strong\u003e(a, b, c) Histopathology of brain tissue from the first surgery in September 2017 showing angiomatous areas. (d, e, f) Histopathology of tissue from the second surgery in August 2019 showing angiomatous areas and calcification in the cerebellum. (g, h) Histopathology of brain tissue from the third surgery in November 2019 showing angiomatous areas and perivascular inflammatory cell infiltration. (i) Histopathology of brain tissue from the fourth surgery in October 2024 showing angiomatous areas. All slides stained with hematoxylin and eosin.\u003c/p\u003e","description":"","filename":"figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9133567/v1/41977dd7ec6a036d95e8b335.jpg"},{"id":106404015,"identity":"d8e6bdd9-ba79-47e4-8a0f-38d7f53c67bf","added_by":"auto","created_at":"2026-04-08 09:15:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2388314,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9133567/v1/b2af2ac6-6d2c-4e63-a8d6-6f3fad27a620.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Eight-year progression of leukoencephalopathy with calcifications and cysts in a patient with Labrune syndrome who underwent multiple surgeries: A case report","fulltext":[{"header":"Background","content":"\u003cp\u003eLeukoencephalopathy with intracranial calcifications and cysts (LCC), also known as Labrune syndrome, is a rare hereditary cerebral microangiopathy that was first reported by Labrune et al. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] in 1996. It is characterized by a neuroimaging triad of diffuse and asymmetric leukoencephalopathy, extensive cerebral calcifications, and parenchymal brain cysts. The core clinical manifestations of LCC include progressive pyramidal or cerebellar signs, cognitive impairment, and epileptic seizures [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Although most patients present during childhood or young adulthood, several cases of late, adult-onset LCC have been reported [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Histopathologically, angiomatous changes and cystic gliotic lesions are the pathological hallmarks of LCC [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Recently, Jenkinson et al. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] identified biallelic variants in the \u003cem\u003eSNORD118\u003c/em\u003e gene as the underlying cause of LCC.\u003c/p\u003e \u003cp\u003eHere, we report a case of LCC in a Chinese woman who underwent five brain surgeries over an 8-year period, to describe the pathological progression of LCC over time. The results are reported according to the CARE guidelines.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 54-year-old woman was admitted to our hospital via the emergency unit in May 2025 because of status epilepticus. She reported experiencing impairments in memory and concentration. Although she had no family history of a hereditary disease or similar illness, the multidisciplinary neuro-oncology team at our center had suspected LCC and recommended genetic testing 5 years previously; however, the patient had declined. In March 2021, cerebral magnetic resonance imaging (MRI) had revealed multiple cysts, calcifications, and diffuse asymmetric white matter lesions (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea\u0026ndash;d). In 2025, cerebral MRI revealed progression and enlargement of the asymmetric white matter lesions, with additional cysts (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ee\u0026ndash;h).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe patient had undergone craniotomies in September 2017, August 2019, November 2019, and October 2024 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The first craniotomy, in September 2017, was to remove lesions in the left temporal lobe that had been discovered on diagnostic imaging. In August 2019, a large cerebellar cyst was surgically removed because of clinical signs of increased intracranial pressure. The patient subsequently experienced an intracranial hemorrhage, and a left parietal lobe cyst was removed in November 2019. In early 2020, 3 months after the third surgery, the patient developed epileptic seizures, bradyphrenia, and memory impairment and was admitted to our hospital for further evaluation and treatment. Initially, the seizures were infrequent and responded well to anticonvulsant therapy. However, new cysts subsequently appeared, and the patient developed progressive motor symptoms, manifesting as right-sided weakness and slurred speech. She had been diagnosed with hypertension in 2023, with intermittent unstable blood pressure, but had not received antihypertensive medication. In October 2024, she had undergone a decompressive craniectomy at another hospital to resect an intracranial space-occupying lesion owing to severe midline shift of the brain. Owing to imaging results and the status epilepticus, resection of the left parietal lesion was recommended, with concurrent cranioplasty of the right temporal and parietal regions. The patient subsequently underwent a fifth surgery in our hospital in May 2025.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eHistopathologic examination of brain tissue from the fifth surgery revealed white matter with a spectrum of microangiopathic changes. The cerebral white matter exhibited angiogenesis and hemorrhage, with changes ranging from dilated vessels with thickened and hyalinized walls to severely sclerotic vessels with mural deposition of fibrinoid material and varying degrees of stenosis, as well as a few obliterated vessels (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea\u0026ndash;c). Additionally, the walls of the blood vessels showed signs of acute and chronic inflammatory cell infiltration, with perivascular lymphocytic cuffing (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed, e). Other changes to the white matter included microhemorrhage, intense gliosis, and multiple foam cells around the damaged vessels, with focal formation of Rosenthal fibers (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ef\u0026ndash;h). Scattered microcalcifications were also present (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ei). CD34 staining revealed abundant small blood vessels within the cyst wall (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ej), whereas neurofilament and Luxol Fast Blue staining revealed partial myelin and axon loss, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ek, l).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWe subsequently conducted a retrospective analysis of pathological sections from the first four surgeries. The chief histopathological findings in the first surgery were angiomatous changes in the form of abnormal prominent congested vessels, with hyaline changes in the blood vessel walls (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea\u0026ndash;c). Tissue resected during the second surgery to remove the cerebellar space-occupying lesion showed angiomatoid areas and dystrophic calcification in the cerebral parenchyma and vessel walls (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ed\u0026ndash;f). Postoperative pathology of brain tissue resected during the third and fourth surgeries revealed multiple dilated and congested blood vessels as well as angiomatoid areas (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eg\u0026ndash;i). These pathological findings were consistent with a diagnosis of LCC.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCompared with other hereditary cerebral small-vessel diseases, LCC is clinically heterogeneous, with a highly variable disease course [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Headache is the most common neurological symptom because of the increased intracranial pressure resulting from the mass effect induced by cysts, hemorrhage, and cerebral edema. Other common clinical manifestations include hemiplegia and epilepsy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], as in our patient. Although LCC generally shows a slowly progressive clinical course, neuroimaging reveals severe and progressive degenerative changes in the nervous system. The commonly described neuroimaging features of LCC include diffuse bilateral cerebral white matter hyperintensity on T2-weighted imaging (particularly around cysts), increased white matter signal intensity with relative sparing of U-fibers and the corpus callosum, and extensive coarse calcifications in the basal ganglia and brain stem [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLCC has diverse histological manifestations. Its key histological characteristics include angiomatoid hyperplasia, thickening and degeneration of blood vessel walls, lymphocyte aggregation, and glial cell proliferation. Phagocytes accumulate around the blood vessels in brain tissue, accompanied by hemosiderin deposition, scattered microcalcifications, gliosis, formation of Rosenthal fibers and eosinophilic bodies, and demyelination. These changes further lead to cerebral tissue degeneration, necrosis, calcification, and hemorrhage [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis case demonstrates the progressive histopathological changes of LCC, specifically the microcystic degeneration caused by persistent and diffuse cerebral microangiopathy, as well as the degeneration of brain tissue induced by the microcystic changes. The slow disease progression in our patient is consistent with the reported slow progression of LCC [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Over the 8-year clinical course, many of the intracranial cysts gradually enlarged, causing a mass effect and compressing adjacent structures such as the ventricles and cerebral peduncles. The enlargement of the cysts may be attributed to the continuous accumulation of fluid in the white matter. Serial histomorphological observations from four consecutive surgeries revealed cystic dilatations of varying sizes in the patient\u0026rsquo;s brain tissue, which enabled us to assess the process underlying cyst formation. The cyst walls were composed of brain tissue, with no lining cells in the cavities. The coalescence of microcysts containing edematous fluid probably contributed to cyst enlargement. The main histopathological findings included edematous changes in the cerebral parenchyma, excessive proliferation of abnormal small blood vessels, gliosis, and microcalcifications.\u003c/p\u003e \u003cp\u003eThe histopathological findings from the first three surgeries showed mainly angiomatous changes including prominent congested blood vessels, multiple cystic areas, foci of dystrophic calcification in the cerebral parenchyma, numerous foci of gliosis, Rosenthal fibers, and histiocytic aggregates. However, pathological sections from the fifth surgery showed no angiomatous proliferation of small blood vessels, but the histopathological changes ranged from dilated blood vessels with thickened and hyalinized walls to severe sclerosis of the vessels with mural deposition of fibrinoid material and varying degrees of stenosis, with a few obliterated vessels accompanied by myxoid changes in the neuropil. Numerous hemosiderin-laden macrophages indicated chronic microhemorrhage. Damaged blood vessels were often associated with perivascular myelin and axonal loss, consistent with ischemic changes rather than demyelination alone. This spectrum of microangiopathic changes suggests a temporal sequence, with vascular sclerosis, obliteration, ischemia, and cyst formation as the final steps.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis 8-year follow-up of a case of LCC confirms its indolent course, gradual cyst enlargement, and a spectrum of progressive microangiopathic changes suggestive of microangiopathy-driven ischemia and cyst formation. This case provides novel insights into the progression of the pathology of LCC.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eLCC\u0026nbsp; \u0026nbsp;\u0026nbsp;Leukoencephalopathy with intracranial calcifications and cysts\u003c/p\u003e\n\u003cp\u003eMRI \u0026nbsp; \u0026nbsp; Magnetic resonance imaging\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the First Hospital of Hebei Medical University.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent has been obtained from the patient to publish her case details and the associated images.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe work was supported by Foundation for Excellent Clinical Medical Talent Project of Hebei Province, China [grant number ZF2024036], the Medical Science Research Program of Hebei Province, China [grant number 20260349], and the Science and Technology Program of Hebei Province, China [grant number 236Z7747G].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLL conceptualized the paper. SD, YX, XS, and XL collected the data. LL wrote the original draft, and LL and YL revised the manuscript. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLabrune P, Lacroix C, Gouti\u0026egrave;res F, de Laveaucoupet J, Chevalier P, Zerah M, et al. Extensive brain calcifications, leukodystrophy, and formation of parenchymal cysts: a new progressive disorder due to diffuse cerebral microangiopathy. Neurology. 1996;46:1297\u0026ndash;301. doi:10.1212/WNL.46.5.1297.\u003c/li\u003e\n\u003cli\u003ePaff M, Samuel N, Alsafwani N, Paul D, Diamandis P, Climans SA, et al. Leukoencephalopathy with brain calcifications and cysts (Labrune syndrome) case report: diagnosis and management of a rare neurological disease. BMC Neurol. 2022;22:10. doi:10.1186/s12883-021-02531-y.\u003c/li\u003e\n\u003cli\u003eCorboy JR, Gault J, Kleinschmidt-DeMasters BK. An adult case of leukoencephalopathy with intracranial calcifications and cysts. Neurology. 2006;67:1890\u0026ndash;2. doi:10.1212/01.wnl.0000244470.06748.18.\u003c/li\u003e\n\u003cli\u003eArmstrong MJ, Hacein-Bey L, Brown H. Cerebroretinal microangiopathy with calcifications and cysts: demonstration of radiological progression. J Comput Assist Tomogr. 2009;33: 571\u0026ndash;2. doi:10.1097/RCT.0b013e31818c0957.\u003c/li\u003e\n\u003cli\u003eCoeytaux A, Lobrinus JA, Horvath J, Kurian M, Vargas MI. Late onset of leucoencephalopathy with cerebral calcifications and cysts. J Neuroradiol. 2011;38: 319\u0026ndash;20. doi:10.1016/j.neurad.2010.08.004.\u003c/li\u003e\n\u003cli\u003eKaffenberger T, Valko PO, von Meyenburg J, Bar\u0026aacute;th K, Hewer E, Heppner FL, et al. A case of late onset leukoencephalopathy with cerebral calcifications and cysts in a 59-year-old woman. Eur J Neurol. 2009;16: 278\u0026ndash;81. doi:10.1111/j.1468-1331.2008.02392.x.\u003c/li\u003e\n\u003cli\u003eUmmer K, Salam KA, Noone ML, Pradeep Kumar VG, Mampilly N, Sivakumar S. Leukoencephalopathy with intracranial calcifications and cysts in an adult: case report and review of literature. Ann Indian Acad Neurol. 2010, 13, 299\u0026ndash;301. doi:10.4103/0972-2327.74198.\u003c/li\u003e\n\u003cli\u003eNagae-Poetscher LM, Bibat G, Philippart M, Rosemberg S, Fatemi A, Lacerda MT, et al. Leukoencephalopathy, cerebral calcifications, and cysts: new observations. Neurology. 2004;62:1206\u0026ndash;9. doi:10.1212/01.WNL.0000119341.59445.CF.\u003c/li\u003e\n\u003cli\u003eJenkinson EM, Rodero MP, Kasher PR, Uggenti C, Oojageer A, Goosey LC, et al. Mutations in \u003cem\u003eSNORD118\u003c/em\u003e cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts. Nat Genet. 2016;48:1185\u0026ndash;92. doi:10.1038/ng.3661.\u003c/li\u003e\n\u003cli\u003eSener U, Zorlu Y, Men S, Bayol U, Zanapalioglu U. Leukoencephalopathy, cerebral calcifications, and cysts. AJNR Am J Neuroradiol. 2006;27:200\u0026ndash;3.\u003c/li\u003e\n\u003cli\u003eMa Y, Zhang X, Cheng C, Xu Q, Di H, Zhao J, et al. Leukoencephalopathy with calcifications and cysts: a case report. Med (Baltim). 2017;96:e7597. doi:10.1097/MD.0000000000007597.\u003c/li\u003e\n\u003cli\u003eStephani C, Pfeifenbring S, Mohr A, Stadelmann C. Late-onset leukoencephalopathy with cerebral calcifications and cysts: case report and review of the literature. BMC Neurol. 2016;16:19. doi:10.1186/s12883-016-0543-1.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Labrune syndrome, Leukoencephalopathy, Intracranial cysts, Intracranial calcifications","lastPublishedDoi":"10.21203/rs.3.rs-9133567/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9133567/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eLeukoencephalopathy with intracranial calcifications and cysts (LCC), also known as Labrune syndrome, is a rare genetic microangiopathy caused by biallelic mutations in \u003cem\u003eSNORD118\u003c/em\u003e. The mechanisms by which loss-of-function mutations in \u003cem\u003eSNORD118\u003c/em\u003e develop into leukoencephalopathy, calcifications, and intracranial cysts remains unknown.\u003c/p\u003e\u003ch2\u003eCase Presentation:\u003c/h2\u003e \u003cp\u003eWe report the case of a 54-year-old woman with LCC who was admitted for an acute onset of epilepsy for 5 days. She had a history of intermittent resection of multiple intracranial space-occupying lesions for 8 years and epilepsy for 5 years. She underwent four neurosurgical interventions over an 8-year period. We obtained the pathological sections from these four surgeries and retrospectively analyzed the pathological progression of LCC. Histopathological analysis revealed that angiomatoid hyperplasia was an early histomorphological manifestation of LLC, suggesting that it induced changes in the surrounding brain tissue, aggregation of phagocytes, and subsequent cystic lesions.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe basic histopathological abnormalities of LCC were angiomatoid hyperplasia and obliterative microangiopathy. The 8-year follow-up revealed gradual cyst enlargement (likely from edematous microcyst fusion) and microangiopathic progression (from angiomatous proliferation to vascular sclerosis, obliteration, ischemia, and cyst formation), supporting the pathogenesis of microangiopathy-driven ischemia and cyst formation.\u003c/p\u003e","manuscriptTitle":"Eight-year progression of leukoencephalopathy with calcifications and cysts in a patient with Labrune syndrome who underwent multiple surgeries: A case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-07 16:49:25","doi":"10.21203/rs.3.rs-9133567/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-26T23:55:57+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-24T09:27:38+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-21T01:30:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"265487325884557849820913932409020672119","date":"2026-04-19T19:46:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"326479926824500618080178038406926994712","date":"2026-04-16T06:28:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"302738587624230580593540018222914816939","date":"2026-04-15T13:29:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"65536592877640969490759928438455189142","date":"2026-04-15T12:42:27+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-15T10:32:35+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-20T16:30:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-17T12:33:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-17T12:33:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2026-03-16T05:55:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"353287ff-4ac5-4924-bd82-9f774be588a7","owner":[],"postedDate":"April 7th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-15T10:42:58+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-07 16:49:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9133567","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9133567","identity":"rs-9133567","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}